Cronstein B N, Levin R I, Philips M, Hirschhorn R, Abramson S B, Weissmann G
Department of Medicine, New York University Medical Center, NY 10016.
J Immunol. 1992 Apr 1;148(7):2201-6.
We have recently demonstrated that human neutrophils (PMN) possess two different classes of adenosine receptors (A1 and A2) that, when occupied, promote chemotaxis and inhibit the generation of reactive oxygen species (e.g., O2- and H2O2), respectively. We have previously demonstrated that adenosine protects endothelial cells (EC) from injury by stimulated neutrophils (PMN) both by diminishing generation of H2O2 and inhibiting adherence of PMN to EC. We therefore determined whether occupancy of A1 or A2 adenosine receptors regulated adherence of PMN to EC. At concentrations similar to those required to inhibit release of O2- by ligation of A2 receptors, both adenosine (IC50 = 56 nM) and 5'N-ethylcarboxamidoadenosine (NECA, IC50 = 8 nM), the most potent A2 agonist, inhibited adherence to EC by stimulated PMN (FMLP, 0.1 microM). In direct contrast, the specific A1 agonists N6-phenylisopropyladenosine and N6-cyclopentyladenosine (CPA) promoted PMN adherence to EC at concentrations of 1-100 nM. To further investigate the mechanisms by which adenosine receptor agonists affected the adherence of stimulated PMN we examined the effect of NECA (A2) and CPA (A1) on the adherence of PMN to fibrinogen (a ligand for the beta 2 integrin CD11b/CD18) and to gelatin. In a dose-dependent manner (IC50 = 2 nM), NECA inhibited the adherence of FMLP-treated PMN to fibrinogen- but not gelatin-coated plates. In contrast, CPA (A1) promoted adherence of stimulated PMN to gelatin-(EC50 = 13 pM) but not fibrinogen-coated plates. Theophylline (10 microM), an adenosine receptor antagonist, reversed the inhibition by NECA (0.3 microM) of stimulated neutrophil adherence to fibrinogen. These observations not only confirm the presence of A1 and A2 receptors on PMN but also suggest two opposing roles for adenosine in inflammation. Occupancy of A1 receptors promotes neutrophil adherence to endothelium and chemotaxis (a proinflammatory role) whereas occupancy of A2 receptors inhibits adherence and generation of toxic oxygen metabolites (an antiinflammatory role).
我们最近证明，人类中性粒细胞（PMN）拥有两类不同的腺苷受体（A1和A2），当它们被占据时，分别促进趋化作用并抑制活性氧物质（如O2-和H2O2）的产生。我们之前证明，腺苷通过减少H2O2的产生和抑制PMN与内皮细胞（EC）的黏附，保护内皮细胞免受受刺激的中性粒细胞（PMN）的损伤。因此，我们确定A1或A2腺苷受体的占据是否调节PMN与EC的黏附。在与通过A2受体连接抑制O2-释放所需浓度相似的浓度下，腺苷（IC50 = 56 nM）和最有效的A2激动剂5'-N-乙基羧酰胺腺苷（NECA，IC50 = 8 nM）均抑制受刺激的PMN（FMLP，0.1 microM）与EC的黏附。与此形成直接对比的是，特异性A1激动剂N6-苯基异丙基腺苷和N6-环戊基腺苷（CPA）在1-100 nM的浓度下促进PMN与EC的黏附。为了进一步研究腺苷受体激动剂影响受刺激的PMN黏附的机制，我们研究了NECA（A2）和CPA（A1）对PMN与纤维蛋白原（β2整合素CD11b/CD18的配体）和明胶黏附的影响。NECA以剂量依赖性方式（IC50 = 2 nM）抑制经FMLP处理的PMN与纤维蛋白原包被的平板的黏附，但不抑制与明胶包被平板的黏附。相比之下，CPA（A1）促进受刺激的PMN与明胶包被平板的黏附（EC50 = 13 pM），但不促进与纤维蛋白原包被平板的黏附。腺苷受体拮抗剂茶碱（10 microM）逆转了NECA（0.3 microM）对受刺激的中性粒细胞与纤维蛋白原黏附的抑制作用。这些观察结果不仅证实了PMN上存在A1和A2受体，还表明腺苷在炎症中具有两种相反的作用。A1受体的占据促进中性粒细胞与内皮的黏附和趋化作用（促炎作用），而A2受体的占据抑制黏附和有毒氧代谢产物的产生（抗炎作用）。
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